Non-interventional study protocol Strontium ranelate (ATC M05BX03) Title European Program of Post-Authorization Safety Studies for Protelos®/Osseor® through EU-ADR Alliance Protocol version 3.0 identifier Date of last version of 7 January 2015 protocol EU PAS register number Study not registered yet Active substance Strontium ranelate (ATC M05BX03) Medicinal product Protelos®/Osseor® Product reference EU/1/04/288/001-006 (Protelos®) EU/1/04/287/001-006 (Osseor®) Procedure number EMEA/H/C/000560/ANX 034 EMEA/H/C/000561/ANX 034 Marketing authorization Les Laboratoires Servier holder(s) Joint PASS No Research question and The aims of this PASS program are: objectives 1. To study the effectiveness of the newly established risk minimization measures by characterizing utilization patterns of SR and estimating the prevalence of contraindications and restrictions of indication amongst incident and prevalent SR users 2. To estimate and compare the incidence rates of cardiac and thromboembolic events in new users of SR and new users of bisphosphonates Country(-ies) of study Denmark, Italy, Netherlands, Spain, and United Kingdom. Authors Dr. Daniel Prieto-Alhambra, MD MSc PhD Prof. Dr. Miriam CJM Sturkenboom, PharmD, PhD Marketing authorization holder(s) Marketing authorization Les Laboratoires Servier holder(s) 50 rue Carnot 92284 Suresnes cedex France MAH contact person Christine Bouillant Regulatory Affairs Department Manager Email: [email protected] Phone: +33.1.55.72.37.85 Fax: +33.1.55.72.50.44 07/01/15 2/78 1. TABLE OF CONTENTS 1. TABLE OF CONTENTS .................................................................................................... 3 List of tables ............................................................................................................................... 5 List of figures ............................................................................................................................. 5 2. LIST OF ABBREVIATIONS ............................................................................................. 6 3. RESPONSIBLE PARTIES ................................................................................................. 7 4. ABSTRACT ......................................................................................................................... 9 5. AMENDMENTS AND UPDATES .................................................................................. 14 6. MILESTONES ................................................................................................................... 14 7. RATIONALE AND BACKGROUND ............................................................................. 15 7.1. Product ............................................................................................................................ 15 7.2. Regulatory action ............................................................................................................ 15 7.3. Observational studies on strontium ranelate use and cardiovascular risk ...................... 16 8. RESEARCH QUESTION AND OBJECTIVES ............................................................. 16 9. RESEARCH METHODS ................................................................................................. 17 9.1. Study design .................................................................................................................... 17 9.2. Setting ............................................................................................................................. 17 9.2.1. Source population ......................................................................................................... 18 9.2.2. Study Period ................................................................................................................. 18 9.2.3. Study population ........................................................................................................... 18 9.2.4. Inclusion criteria ........................................................................................................... 18 9.2.5. Exclusion criteria .......................................................................................................... 18 9.2.5.1. Effectiveness of RMM ............................................................................................. 18 9.2.5.2. Incidence rates of safety endpoints .......................................................................... 19 9.2.5.3. Comparative safety study ........................................................................................ 19 9.2.6. Follow-up ..................................................................................................................... 19 9.2.6.1. Effectiveness of risk minimization .......................................................................... 19 9.2.6.2. Safety study ............................................................................................................. 19 9.3. Variables ......................................................................................................................... 20 9.3.1. Safety endpoints ........................................................................................................... 20 9.3.2. Contra-indications and new indications ....................................................................... 21 9.3.3. Exposure ....................................................................................................................... 22 9.3.4. Co-variables (potential confounders) ........................................................................... 23 9.4. Data sources .................................................................................................................... 24 9.4.1. IPCI Database ............................................................................................................... 25 9.4.2. HSD – CSD Longitudinal Patient Database ................................................................. 25 9.4.3. THIN Database ............................................................................................................. 26 9.4.4. Aarhus Database ........................................................................................................... 26 9.4.5. SIDIAP Database.......................................................................................................... 27 07/01/15 3/78 9.5. Study size ........................................................................................................................ 27 9.5.1. RMM effectiveness study ............................................................................................. 28 9.5.2. Safety study .................................................................................................................. 29 9.6. Data management ........................................................................................................... 29 9.6.1. Identification of Unified Medical Language System® (UMLS®) concepts ............... 30 9.6.2. Definition of data extraction algorithm ........................................................................ 31 9.6.3. Event data extraction .................................................................................................... 31 9.6.4. Benchmarking of incidence rates of events .................................................................. 31 9.6.5. Data elaboration............................................................................................................ 31 9.6.6. Missing data.................................................................................................................. 32 9.6.7. Data sharing .................................................................................................................. 32 9.7. Data analysis ................................................................................................................... 32 9.7.1. Statistical elements ....................................................................................................... 32 9.7.2. Effectiveness of the RMM............................................................................................ 32 9.7.2.1. Utilization of Strontium ranelate ............................................................................. 32 9.7.2.2. Prevalence of contra-indications and new restrictions ............................................ 33 9.7.3. Safety Studies ............................................................................................................... 34 9.7.3.1. Characteristics of study cohorts ............................................................................... 34 9.7.3.2. Absolute rates of safety endpoints ........................................................................... 34 9.7.3.3. Relative risks ........................................................................................................... 35 9.7.4. Pooling .......................................................................................................................... 35 9.7.5. Sensitivity analyses ...................................................................................................... 35 9.8. Quality control ................................................................................................................ 35 9.9. Limitations of the research methods ..............................................................................